Chronic wounds induced by the impaired wound healing especially in diabetic patients and aged individuals are still a major unsolved biomedical challenge. This has highlighted the importance and urgency of studying the novel mechanisms of the impaired wound healing and exploring now therapeutic options. MicroRNAs (miRNAs) have emerged as a novel class of noncoding RNAs with tremendous biological functions. The goals of this project are to determine the miRNA mechanism and therapeutics of impaired wound healing. Using RCR based array and deep-sequencing analysis as well as qRT-PCR, we identified a group of miRNAs that are aberrantly expressed in bone marrow (BM)-derived endothelial progenitor cells (EPCs) isolated from diabetic and aged individuals and mice. Among them, let-7 family members, let-7b, let-7c, let-7d, and let-7d* are significantly increased. The hypothesis of this proposal is that Let-7 family members play important roles in the impaired cellular functions of EPCs and impaired wound healing in diabetes and aged individuals via their target genes. miRNA-reprogrammed smart EPCs via modulators of let-7 family may represent a novel effective therapy for chronic wounds. We will test our hypothesis via three specific aims: Aim 1 will determine the effects of let-7 family members on the migration, proliferation and apoptosis of EPCs in vitro. Aim 2 will determine the effects of let-7-reprogrammed autologous EPCs on wound angiogenesis and wound healing in diabetic and aged mice in vivo. Aim 3 will determine the molecular mechanisms of let-7-mediated biological effects. The biological role of let-7 family on refractory wounds via gene reprogramming in EPCs is an unexplored research field. The proposed study will utilize the latest cellular, molecular, and whole animal approaches to target the major unsolved biomedical challenge: chronic wounds. Uncovering the novel molecular mechanisms and therapeutics of the impaired wound healing at translational level via miRNAs may open a new scientific paradigm in chronic wounds.